All Depressed Brains Are Not the Same

Different ADs work on different parts of the brain.
From Nancy Schimelpfening

All Depressed Brains Are Not the Same

Very often I am asked to recommend a good antidepressant. My answer, other than the obvious, “Please see your doctor for medical advice”, is this: “the one that works for you”!

Each class of antidepressant works on your brain chemistry in a different way. Dr. Abbott Lee Granoff, a noted expert in the field of panic disorder and depression, says the following: “There are currently 23 antidepressants on the market (Guide Note: this figure is for the US only. There are some antidepressants available in other countries which are not approved for use in the US). Each increases certain neurotransmitters in the brain and each can do this in slightly different parts of the brain.”1 So, while one person may get relief from having their serotonin boosted, another may need a drug that affects both serotonin and norepinephrine. Still another person may need an entirely different sort of medication, such an anticonvulsant or a mood stabilizer like lithium. Further, a person who does well on a medication such as Zoloft may not do as well on Prozac, even though both belong to the same class.2 Each person will be very different in their medication needs.

Just like the wide variety of brains, there are a wide variety of antidepressants. Broadly speaking, these fall into the following classes: monoamine oxidase inhibitors (MAOIs), tricyclics (TCAs) and selective serotonin reuptake inhibitors (SSRIs). There are also several newer medications that are unique in their mechanism of action.

Monoamine Oxidase Inhibitors

The monoamine oxidase inhibitors (MAOIs) were some of the first antidepressant medications developed. The neurotransmitters responsible for mood, primarily norepinephrine and serotonin, are also known as monoamines. Monoamine oxidase is an enzyme which breaks these substances down. Monoamine oxidase inhibitors, as the name implies, inhibits this enzyme, thus allowing a greater supply of these chemicals to remain available.

MAOIs have fallen out of favor as first-line antidepressants because they offer several disadvantages to patients compared to newer medications. Potentially fatal drug-drug interactions can occur with MAOIs when combined with a variety of drugs which are serotonin agonists (the “serotonin syndrome”) or norepinephrine agonists.3 People on these medications must also follow strict dietary restrictions of foods rich in tyramine4 to avoid potential hypertensive (high blood pressure) crisis. A major adverse effect that occurs on MAOIs alone is hypotension (low blood pressure), which can present as fatigue and may mimic worsening of the underlying depressive syndrome. For this reason, the blood pressure should always be monitored when using these antidepressants.5


Tricyclics, also known as heterocyclics, came into broad use in the 1950’s. These drugs inhibit the nerve cell’s ability to reuptake serotonin and norepinephrine, thus allowing a greater amount of these two substances to be available for use by nerve cells.

In addition to acting on norepinephrine and serotonin, tricyclics exhibit similar effects on histamine and acetylcholine. This is responsible for the troublesome side-effects we usually associate with these medications, such as dry mouth, blurry vision, weight gain and sedation.6

With tricyclics, a patient’s medical history must be closely considered. These medications may cause orthostatic hypotension (dizziness upon standing); rapid heartbeat, sometimes with palpitations; and may aggravate preexisting heart conditions. Patients with a history of seizures or head injury must also be cautious as these drugs may cause seizure.7

Selective Serotonin Reuptake Inhibitors

Claims of decreased side-effects and increased safety relative to the older medications have made this class of antidepressant very popular in recent years. Five drugs currently belong to this class: fluoxetine (Prozac), citalopram (Celexa), fluvoxamine (Luvox), sertraline (Zoloft), and paroxetine (Paxil).

SSRI stands for Selective Serotonin Reuptake Inhibitor. These medications work, as the name implies, by blocking the presynaptic serotonin transporter receptor.8 This drug differs from the tricyclics in that it’s action is specific to serotonin only. It’s effect on norepinephrine is indirect, through the fact that falling serotonin “permits” norepinephrine to fall so preserving serotonin preserves norepinephrine.9

SSRIs, through their specificity, have the advantage of not affecting histamine and acetylcholine. The implication is that although they are not without side-effects, they do not create the same bothersome side-effects as the tricyclics.

Newer Mechanisms

Five newer medications which do not fit into the above categories are: buproprion (Wellbutrin), nefazodone (Serzone), trazodone (Desyrel), venlafaxine (Effexor), and mirtazapine (Remeron).

The mechanism of bupropion’s antidepressant activity is poorly understood, but is thought to be mediated through noradrenergic or dopaminergic pathways or both.10 This medication lacks the sexual side-effects so common to the SSRIs and is popular for patients who exhibit a lack of energy, psychomotor slowness and excessive sleep.

Nefazodone and it’s precursor trazodone both inhibit neuronal reuptake of serotonin and, to a lesser extent, norepinepherine. They also blocks postsynaptic 5-HT2 receptors. Nefazodone has weak affinity for cholinergic and a1- adrenergic receptors and, therefore, is associated with less sedation and orthostasis than trazodone.11

Venlafaxine is a compound that is structurally unrelated to other antidepressants.12 Like the TCAs, venlafaxine inhibits the neuronal uptake of both serotonin and norepinepherine. Venlafaxine has dose-dependent, sequential effects on the uptake pumps for serotonin and then norepinephrine.. At 75 mg/day, venlafaxine is predominantly a serotonin reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it produces comparable norepinephrine uptake inhibition to an NSRI such as desipramine.13

Mirtazapine is the most recently released of these four and is the first a2-antagonist marketed as an antidepressant.14 Mirtazapine’s unique mechanism of action does not involve enzyme inhibition or blockade of neurotransmitter reuptake. Mirtazapine increases the release of norepinepherine from central noradrenergic neurons by blocking the presynaptic inhibitory alpha-2 autoreceptors. It spares the alpha-1 postsynaptic receptor and therefore results in net increase noradrenergic transmission. As a second presynaptic receptor blocking function, mirtazapine blocks the inhibitory alpha-2 heteroreceptors located on serotonergic neurons, resulting in increase release of serotonin. Postsynaptically, mirtazapine has low affinity for the 5-HT1A receptor, thus allowing serotonin released into the synapse to bind to and stimulate this receptor. However, it blocks postsynaptic 5-HT2 and 5-HT3 receptors. Stimulation of the 5-HT2 receptor is thought to be responsible for the serotonergic side effects of insomnia, agitation, and sexual dysfunction seen with the SSRI’s and 5-HT3 receptor stimulation is thought to mediate nausea seen with these agents.15, 16, 17 Therefore, mirtazapine’s receptor blocking profile prevents the side-effects seen with nonselective activation of serotonin receptors which occurs with pure reuptake blockers.


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